Nucleic acids encoding human anti-kir antibodies

Abstract

Compositions and methods for regulating an immune response in a subject are described. More particularly, described are human antibodies that regulate the activity of NK cells and allow a potentiation of NK cell cytotoxicity in mammalian subjects, and antibodies having antigen-binding properties similar to those of human monoclonal antibody 1-7F9 or 1-4F1. Described also are also fragments and derivatives of such antibodies, as well as pharmaceutical compositions comprising the same and their uses, particularly for use in therapy, to increase NK cell activity or cytotoxicity in subjects.

What is claimed is: 
     
       1. An isolated nucleic acid encoding a variable heavy (VH) chain of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4, or a vector comprising said isolated nucleic acid, wherein said nucleic acid is selected from the following:
 (i) a nucleic acid encoding a VH chain of an antibody or antibody fragment, said heavy chain comprising a CDR1 region corresponding to amino acid residues 31-35 set forth in SEQ ID NO:17; a CDR2 region corresponding to amino acid residues 50-65 set forth in SEQ ID NO:17; and a CDR3 region corresponding to amino acid residues 99-112 set forth in SEQ ID NO:17; and 
 (ii) a nucleic acid encoding a VH chain comprising the heavy chain CDR1, CDR2 and CDR3 regions recited in (i), and which VH chain is at least 90% identical to a VH chain comprising amino acids having the sequence set forth in SEQ ID NO: 17. 
 
     
     
       2. The isolated nucleic acid encoding the VH chain according to  claim 1 , wherein the isolated nucleic acid encodes a VH chain comprising amino acids having the sequence set forth in SEQ ID NO: 17. 
     
     
       3. An isolated cell containing the isolated nucleic acid encoding the VH chain according to  claim 2 , and further comprising a nucleic acid encoding a VL chain that comprises amino acid having the sequence set forth in SEQ ID NO: 15, wherein said nucleic acid encoding the VH chain and said nucleic acid encoding the VL chain may be on the same or different nucleic acid constructs. 
     
     
       4. A method of culturing a cell according to  claim 3  under conditions that result in the expression of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4. 
     
     
       5. An isolated nucleic acid encoding a variable light (VL) chain of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4, or a vector comprising said isolated nucleic acid, wherein said nucleic acid is selected from the following:
 (i) a nucleic acid encoding a VL chain of an antibody or antibody fragment, said light chain comprising a CDR1 region corresponding to amino acid residues 24-34 set forth in SEQ ID NO:15; a CDR2 region corresponding to amino acid residues 50-56 set forth in SEQ ID NO:15; and a CDR3 region corresponding to amino acid residues 89-97 set forth in SEQ ID NO:15; and 
 (ii) a nucleic acid encoding a VL chain comprising the light chain CDR1, CDR2 and CDR3 regions recited in (i), and which VL chain is at least 90% identical to a VL chain comprising amino acids having the sequence set forth in SEQ ID NO: 15. 
 
     
     
       6. The isolated nucleic acid encoding the VL region according to  claim 5 , wherein the isolated nucleic acid encodes a VL chain comprising the amino acids having the sequence set forth in SEQ ID NO: 15. 
     
     
       7. An isolated nucleic acid or nucleic acids, which separately or in combination, encode the variable heavy (VH) chain and the variable light (VL) chain of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4, wherein said VH chain is encoded by:
 (1)(i) a nucleic acid encoding a VH chain of an antibody or antibody fragment, said heavy chain comprising a CDR1 region corresponding to amino acid residues 31-35 set forth in SEQ ID NO:17; a CDR2 region corresponding to amino acid residues 50-65 set forth in SEQ ID NO:17; and a CDR3 region corresponding to amino acid residues 99-112 set forth in SEQ ID NO:17; or 
 (1)(ii) a nucleic acid encoding a VH chain comprising the heavy chain CDR1, CDR2 and CDR3 regions recited in (1)(i), and which VH chain is at least 90% identical to the VH chain comprising amino acids having the sequence set forth in SEQ ID NO: 17; and wherein said VL chain is encoded by: 
 (2)(i) a nucleic acid encoding a VL chain of an antibody or antibody fragment, said light chain comprising a CDR1 region corresponding to amino acid residues 24-34 set forth in SEQ ID NO:15; a CDR2 region corresponding to amino acid residues 50-56 set forth in SEQ ID NO:15; and a CDR3 region corresponding to amino acid residues 89-97 set forth in SEQ ID NO:15; or 
 (2)(ii) a nucleic acid encoding a VL chain comprising the light chain CDR1, CDR2 and CDR3 regions recited in (2)(i), and which VL chain is at least 90% identical to the VL chain comprising the amino acids sequence set forth in SEQ ID NO: 15, 
 wherein said nucleic acid(s) encoding the VH and VL chains may be contained on the same or different nucleic acid constructs. 
 
     
     
       8. An isolated cell containing the nucleic acid or nucleic acids according to  claim 7 , wherein said nucleic acid(s) may be on the same or different nucleic acid constructs. 
     
     
       9. A method of culturing a cell according to  claim 8  under conditions that result in the expression of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4. 
     
     
       10. The isolated nucleic acid or nucleic acids according to  claim 7 , encoding the variable heavy (VH) chain and the variable light (VL) chain of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4, said nucleic acid(s) comprising:
 (1) a nucleic acid encoding a VH chain comprising a CDR1 region corresponding to amino acid residues 31-35 set forth in SEQ ID NO:17; a CDR2 region corresponding to amino acid residues 50-65 set forth in SEQ ID NO:17; and a CDR3 region corresponding to amino acid residues 99-112 set forth in SEQ ID NO:17, which VH chain is at least 95% identical to the VH chain comprising amino acids having the sequence set forth in SEQ ID NO: 17; and 
 (2) a nucleic acid encoding a VL chain comprising a CDR1 region corresponding to amino acid residues 24-34 set forth in SEQ ID NO:15; a CDR2 region corresponding to amino acid residues 50-56 set forth in SEQ ID NO:15; and a CDR3 region corresponding to amino acid residues 89-97 set forth in SEQ ID NO:15, which VL chain is at least 95% identical to the VL chain comprising amino acids having the sequence set forth in SEQ ID NO: 15, 
 wherein said nucleic acid(s) encoding the VH and VL chains may be contained on the same or different nucleic acid constructs. 
 
     
     
       11. An isolated cell containing the nucleic acid or nucleic acids according to  claim 10 , wherein said nucleic acid(s) may be on the same or different nucleic acid constructs. 
     
     
       12. A method of culturing a cell according to  claim 11  under conditions that result in the expression of an antibody or antigen-binding fragment thereof that binds to each one of human KIR2DL1, human KIR2DL2, and human KIR2DL3, but which does not bind human KIR2DS4. 
     
     
       13. The isolated nucleic acid or nucleic acids of any one of  claims 1 - 7 , which encodes human framework residues.